Contrary to the downregulation of
Contrary to the downregulation of S1PR family GPCRs, CLL cells have increased mRNA expression of the lysophosphatidic Alisol B 23-acetate (LPA) family receptors LPAR1, LPAR3 and LPAR4 compared to normal B cells . Increased LPAR1 mRNA has been shown to be associated with more aggressive disease  and LPA signaling was found to act as a survival factor by protecting primary CLL cells from spontaneous and chemotherapy-induced apoptosis . Further study revealed that treatment of B cell lines with LPA induced vascular endothelial growth factor (VEGF) expression via activation of c-Jun N-terminal kinases (JNK) and nuclear factor-kappa B (NF-κB) and protected cells against apoptosis , . Cannabinoid signaling pathways have been investigated for potentially containing novel therapeutic targets in CLL/SLL. The cannabinoid receptor transcripts CNR1 and CNR2 were found to be overexpressed in CLL and SLL compared to normal B cells and high CNR1 expression was significantly associated with shorter overall survival , . Although treatment with cannabinoids reduced viability of CLL cells in culture, the simultaneous death of healthy cells suggested that targeting cannabinoid receptors could have poor therapeutic value . Numerous GPCRs have significantly altered expression in CLL as compared to healthy lymphocytes and these expression patterns can serve as biomarkers of disease subtype or progression. For example, tachykinin receptor TACR1 mRNA is overexpressed in CLL patient cells compared to normal B lymphocytes and expression is higher in aggressive IGHV-unmutated CLL compared to indolent IGHV-mutated CLL . Conversely, CLL mononuclear leukocytes contain fewer beta-2 adrenergic receptors (ADRB2) than healthy cells and increased dysfunction of the receptor complex is correlated with disease progression . ADRB2 agonists have been shown to induce apoptotic cell death in CLL cells alone and synergistically with other agents  and expression of alpha-2 adrenergic receptors has also been described in CLL . Multiple GPCRs are believed to affect cyclic adenosine monophosphate (cAMP) and calcium signaling in CLL. RNA transcripts from the adenosine receptors ADORA2A and ADORA2B and purinergic receptor P2RY11 were found to be expressed in CLL lymphocytes it is believed that adenosine induces cAMP accumulation via ADORA2A while adenosine triphosphate (ATP) induces cAMP through P2RY11 . The calcitonin receptor CALCR mRNA and protein were shown to be overexpressed in CLL cells compared to healthy B cells and it is suspected that an increase in CALCR expression increases the concentration of intracellular calcium to promote lymphocyte activation and proliferation . In addition, mRNA from the cysteinyl leukotriene receptor CYSLTR1 was found to be well-expressed in CD19+ CLL cells, albeit at lower levels than normal CD19+ cells, and was found to mediate intracellular calcium and cell migration in response to leukotrienes . Notable oncogenic hallmarks such as increased DNA synthesis, cell cycle progression, and adaptation to the tumor microenvironment are all influenced by GPCRs in CLL. The endothelin receptor EDNRA was found to be overexpressed at both the mRNA and protein level in CLL cells compared to normal cells and activation of EDNRA via endothelin-1 resulted in increased proliferation, cell cycle progression and mitogen-activated protein kinase (MAPK) signaling . The acid sensing GPCR GPR65 transcript levels in CLL were significantly correlated with expression of the apoptosis-regulating proteins Bcl-2, Mcl-1 and Bcl-xl, suggesting that GPR65 may aid CLL cells to survive in the acidic tumor microenvironment . Finally, CLL cells express the leukotriene receptor LTB4R (BLT1) protein and treatment of these cells with leukotriene biosynthesis inhibitors inhibited DNA synthesis and antigen expression and thus represent a novel CLL therapeutic .